Brain mapping tools are essential for both our understanding the brain as well as diagnosing dysfunction. A method to noninvasively and precisely stimulate any three-dimensional locus within the human brain would be transformative, both clinically and scientifically. If compatible with modern functional brain imaging methods, such an improved stimulation tool could support unprecedented studies exploring human brain function and connectivity. Clinically, it could support novel screening/diagnostic strategies and improved treatments for diseases such as depression, Parkinson's, and epilepsy which are becoming more frequently treated using invasive stimulation methods (for example with deep-brain stimulating electrodes; DBS). Pulsed ultrasound (US) energy can be used to modulate brain circuit activity and has the characteristics required to achieve targeted stimulation with millimeter spatial resolution anywhere in the brain. Our goal is to translate ultrasound neuromodulation to humans and develop technologies to combine ultrasound-induced neuromodulation with current neuroimaging and electrophysiology methods. The methods we propose to develop will establish a new paradigm in diagnostic medicine and be broadly applicable to neurological disorders as well as increase our ability to understand integrative functions of the brain. Specific Aim 1. Development of a hardware and software platform for identifying optimal pulsed UNMOD waveforms. Milestone: Hardware and software platform that integrates US stimulation with electrophysiological and fMRI data acquisition to establish a systematic approach for assaying the optimal ultrasound neuromodulation (UNMOD) stimulus parameter space. Specific Aim 2. Development of focusing and scanning strategies for deep neurostimulation through the skull using ultrasound. Milestone: Neuromodulation strategies using multiple sources of ultrasound that offer an improvement in spatial resolution of activation, decrease undesirable thermal effects, and increase in activation efficiency. Specific Aim3. Testing focal neurostimulation strategies in the primate brain. We will use this model to test approaches developed in Specific Aims 1 and 2. Milestone: Proof of concept in primates and the selection of optimal focusing and scanning strategies to be tested in humans. Specific Aim 4. Simultaneous ultrasound nerve stimulation, fMRI imaging and EEG recordings in humans. Milestone: Successful integration of UNMOD, fMRI imaging and EEG recordings in humans. At the successful conclusion of this Phase I SBIR we will have developed a number of key technology pieces for translating functional brain mapping with noninvasive ultrasound neuromodulation in humans. These include the ability to stimulate targeted brain regions through the skull, a proof of concept in primates, and successful integration of UNMOT, fMRI and EEG in humans. We will be poised in Phase II to use this technique to compare the functional brain maps of healthy individuals with ones suffering from neurological disorders. PUBLIC HEALTH RELEVANCE: Brain mapping tools are essential for understanding the brain as well as diagnosing brain dysfunction. We propose to use ultrasound to precisely stimulate parts of the brain, noninvasively, in contrast to current invasive stimulation methods. The methods developed will establish a new paradigm in diagnostic medicine, be broadly applicable to neurological disorders such as depression, Parkinson's, and epilepsy, and increase our ability to understand integrative functions of the brain.